1. Field of the Invention
The present disclosure relates to a fusion protein comprising human interleukin-1 receptor antagonist and hybrid Fc.
2. Description of the Related Art
Various monoclonal antibodies or fusion proteins, specifically binding to inflammatory cytokines, such as tumor necrosis factor-α (TNF-α), interleukin (IL)-1, IL-6 or receptor activator for nuclear factor κB ligand (RANKL), have been widely used to develop drugs for the inflammatory diseases. These drugs are targeting the diseases including inflammatory bowel disease (Crohn's disease, ulcerative colitis), rheumatoid arthritis and psoriasis and the like.
Among them, biological TNF-α inhibitors are leading the market at the present. However, its therapeutic applications have been limited by some problems, which include that all patients are not respond to TNF-alpha inhibitors and even if patients were respond to TNF-alpha inhibitors, the patients will not respond to TNF-alpha inhibitors after treatments of long period. Also since TNF-α plays an important role in a defense mechanism against bacterial and viral infections, the use of TNF-α blocker puts the patients at increased risk of serious infection, opportunistic infection and a recurrence of pneumonia. Therefore, there are needs for the development of new therapeutic agents for inflammatory autoimmune disease based on a novel mechanism of action that can replace the existing TNF-blockers.
Meanwhile, IL-1 receptor antagonist (IL-1Ra) is a natural IL-1 blocker found in the body and exerts their effects by competitively binding of IL-1 to its receptor (Fredericks, Zoey L et al., Protein Engineering, Design&Selection (2004) 17 (1): 95-106). In this regards, human recombinant IL-1 receptor antagonist (for example anakinra) has been developed and found to be effective in treating patients suffering from rheumatoid arthritis who do not respond to TNF-α inhibitors (Bresnihan, Ann. Rhem. Dis (2002); St. Clair, E. W. J. Rheumatol. (2002)). However, possibility of immunogenicity due to having extra methionine to produce in bacterial cells and short half-life around 2˜3 hours requiring a daily injection remain to be the problems.
Also IL-1 receptor antagonist Fc fusion proteins had been expected to be effective in treating autoimmune disease by suppressing the activity of IL-1 which is the key factor in maintaining the inflammatory response. However, conventionally used for the construction of the fusion protein was the Fc derived from IgG1, and this caused antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC), which led to the death of target cells. The resulting elimination of target cells may cause other safety concern of therapeutic agents.